Pumping the brakes on dangerous proteins

In a new study, scientists at Northwestern Medicine and the Broad Institute of MIT and Harvard have identified an RNA that regulates production of the CHD2 protein linked to genetic disorders including epilepsy and autism. The findings, which were published in the New England Journal of Medicine, reveal a new potential mechanism for treating these disorders and underscore the importance of studying the human genome.

CHD2: A “Goldilocks gene”

When a gene produces too much protein, it can have devastating consequences on brain development and function. Patients with an overproduction of protein from the chromodomain helicase DNA binding (CHD2) gene can develop a rare and severe neurodevelopmental disorder that renders them non-ambulatory, nonverbal and with profound intellectual delays.

Northwestern researchers previously found that in a subset of patients with epilepsy and autism, the CHD2 gene produces too little protein. The new study, however, examined three patients whose CHD2 gene produced too much protein.

“We call CHD2 a ‘Goldilocks gene,’ because both too little is bad and too much is also bad,” said Gemma Carvill, an assistant professor of neurology, pharmacology and pediatrics at Northwestern University Feinberg School of Medicine and corresponding author of the study.

What’s new

The researchers discovered an RNA that acts like the brake in one’s car to control how much or how little protein is produced by CHD2. When a long non-coding RNA called CHASERR (CHD2 adjacent, suppressive regulatory RNA) is deleted, the “foot” is taken off the “brake,” and CHD2 protein production goes into overdrive.

While most RNAs make proteins, long non-coding RNAs don't make proteins but are crucial for regulating gene activity. Long non-coding RNAs like CHASERR exist in the so-called “Wild West” (99%) of the human genome that is currently understudied.

“There are thousands of long non-coding RNAs, but, until this study, we didn’t know what they did,” Carvill said.

Although previous studies in mice by Igor Ulitsky at the Weizmann Institute have found a link between a CHASERR deletion and how much CHD2 protein is produced, this is the first study to find this link in humans. Ulitsky, an expert in the biology of long non-coding RNAs, also is an author on the paper.

Emma’s story

Emma Broadbent, 8, was the first of the three patients identified for this study. She uses a wheelchair, is non-verbal, uses a feeding tube and has severe intellectual delays. When her dad, Brian Broadbent, learned of Emma’s deletion of CHASERR through her genome sequencing, he began scouring the internet for anyone researching CHD2. He eventually connected with Carvill and other scientists globally, and the resulting research team was able to identify the other two patients with the CHASERR deletion.

“Emma suffers a lot, and this adds purpose to her life because she’s helping science,” said Brian, who is a co-author on the study. “We felt we had a responsibility to push this as forward as much as we can because it's going to impact future children. This is just scratching the surface of something that could be really important. We intuitively understood that this was a lot bigger than just Emma.”

Future treatment potential

Carvill said future studies that attempt to manipulate CHASERR might have success in controlling the amount of CHD2 protein that is produced, thereby leading to more effective treatments for patients.

It is mind-boggling that we only know what 1% of the human genome does, and we have very little idea what the other 99% does.”

Currently, patients with epilepsy are treated with antiseizure medications, but this is treating the symptoms of the disorder, not the actual cause. Additionally, 30% of patients with epilepsy do not respond to current medications.

Ideally, Carvill and her team would like to treat patients with epilepsy and other seizure-related disorders with gene-targeting therapies to target the genetic change at the root of the disorders. Identification of non-coding regions that control gene expression, like CHASERR, is one way her team is thinking about using their knowledge of the human genome to design gene-targeting therapies.

CHASERR’s connection to genetic disorders is probably not an isolated case, Carvill said. Instead, it’s more likely that long non-coding RNAs and non-coding regions are implicated more broadly across human disorders, meriting further exploration of the human genome.

“It is mind-boggling that we only know what 1% of the human genome does, and we have very little idea what the other 99% does,” Carvill said. “We ignore it, and our study highlights why we shouldn't.”